1. Field of the Invention
The present invention relates to novel sensitizing agents for boron neutron capture therapy and therapeutic methods which employ such sensitizing agents.
2. Discussion of the Background
According to the American Association For Brain Tumor, in the United States alone about 20,000 persons develop brain tumors yearly. The most common type of brain tumor is the glioma with an incidence ranging from 31% to 49% of all intracranial tumors and a mortality of greater than 99% in such individuals no matter how radical the surgical procedure. In individuals suffering from such tumors, survival time is usually measured in weeks or months rather than in years.
Gliomas are characterized by a main tumor mass with finger-shaped colonies of neoplastic cells that invade surrounding brain tissue and are dispersed. These tumors are often inaccessible to surgical removal or to standard external beam therapy. The encouraging clinical results with neutron capture therapy (NCT) of glioblastoma using a sulfhydryl borane monomer and continued interest in the preparation of third generation boron compounds for NCT have provided considerable momentum for the treatment of brain and other tumors using this therapeutic modality.
The use of boron compounds for boron neutron capture therapy (BNCT) is a combined modality consisting of the interaction of two components, neutrons and .sup.10 B. Non-radioactive .sup.10 B at 20% natural abundance, has a high neutron capture cross-section (3,850 barns). The .sup.10 B nucleus absorbs a low energy thermal neutron releasing an alpha particle, a lithium atom, and about 100 million times more energy than that which was put in. Since the effect in human tissue is dependent upon both the boron concentration within the irradiated tissue and the total thermal neutron flux, cellular death is not a random phenomenon. Thus, a physical differential is obtained which is unavailable with conventional radiotherapy. None of the normal elements comprising human tissue possesses cross sections for thermal neutrons comparable to .sup.20 B. Because the nuclear fragments from the .sup.10 B(n,.alpha.).sup.7 Li reaction travel only about 10 .mu.m, destructive radiation predominates only in the immediate vicinity of cells having a high .sup.10 B content. The thermal neutrons themselves are of subionizing energy and diffuse relatively harmlessly through tissue until captured by various elements. Thus, the potentially cytotoxic agent is nontoxic to the tumor cells until activated by an externally applied radiation field of neutrons. A major advantage of this binary system is that the time for irradiation can be selected so that the dose of irradiation can be delivered when the ratio of the concentration of the sensitizing agent in the tumor tissue to that in the normal tissue is optimal.
Although significant advances have been made in NCT, because of the inherent difficulty in synthesizing rationally designed hydrolytically stable boron compounds, it is clear that more emphasis should be placed on the chemical and pharmacological aspects. The thymidine analogue, 5-dihydroxyboryl-2'-deoxyuridine (DBDU), Schinazi and Prusoff, J. Org. Chem., vol. 50, pp. 841-847, (1985) a compound has been shown to destroy hamster V-79 cells when irradiated with low energy neutrons. This destruction is a consequence of the .sup.10 B(n,.alpha.).sup.7 Li reaction itself, as well as a concomitant self-sensitization to those radiations provided by the presence of the nucleoside analog in DNA.
The viability of 3'-heteranucleosides, such as racemic 2', 3'-dideoxy-3'-thiacytidine (BCH-189) and 2', 3'-dideoxy-5-fluoro-3'-thiacytidine (FTC), as both anti-human immunodeficiency viruses (HIV) and anti-Hepatitis B virus (HBV) agents has been demonstrated (Choi et al, J. Amer. Chem. Soc., 113:9377-9379, 1991; Doong et al, Proc. Natl. Acad. Sci. U.S.A, 88:8495-8499, 1991; Doong et al, Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Ill. Sep. 29-Oct. 2, 1991; Schinazi et al, National Collaborative Drug Discovery Group, Frontiers in HIV Therapy, San Diego, Calif., Nov. 3.gtoreq.7, 1991; Schinazi et al, Antimicrob. Agents Chemother., 36 (3):1992 (in press); Unpublished results from Hoong et al).
These compounds not only show good activity against these viruses, but also exhibit extremely low toxicity. In addition, they readily permeate cell membranes, are excellent substrates for cellular kinases, and resist many other catabolic processes that are commonly observed with other 2'-deoxycytidine nucleosides (Schinazi et al, National Collaborative Drug Discovery Group, Frontiers in HIV Therapy, San Diego, Calif., Nov. 3-7, 1991).
Analogues of 6-iodo-2-methyl-1,4-naphthoquinol bis(diammonium phosphate) (6-I-MNDP) are known to selectively concentrate in the cells of some human malignant tumors (Brown et al, Eur. J. Nucl. Med., 7(3):115-20, 1982; Carpenter et al, Int. J. Radiat. Oncol. Biol. Phys., 9:51-5, 1983; Mitchell et al, Prog. Clin. Biol. Res., 166:327-35, 1984; Mitchell et al, Experientia, 41:925-8, 1985). These synthetic water-soluble molecules are related chemically to vitamin K (Mitchell et al, Nature, 160:98-99, 1947). Uptake of 6-I-MNDP into malignant cells is significantly higher (15 to 20-fold) than in normal cells under both euoxic and hypoxic conditions (Brown et al, Eur. J. Nucl. Med., 7(3):115-20, 1982; Carpenter et al, Int. J. Radiat. Oncol. Biol. Phys., 9:51-5, 1983). In addition, .alpha.-particle track autoradiographic studies of radiolabeled 6-I-MNDP in mice have demonstrated low uptake into critical radiosensitive tissues, such as bone-marrow, colon, and lung, and high uptake in tumor tissues (Mitchell et al, Experientia, 41:925-8, 1985). The halogen-carbon bond in 6-I-MNDP is metabolically stable in mice. Mitchell (Mitchell, Br. J. Cancer, 29:373-88, 1974) performed studies with radiolabeled MNDP in 203 patients with different malignant tumors. High specific activity preparations were useful in the treatment of some patients with advanced tumors, especially carcinoma of the colon and pancreas and for malignant melanoma. The specificity of 6-I-MNDP has been attributed to the expression of oncogenically associated alkaline phosphatase isoenzyme in certain tumor cells and in particular cell-membrane bound enzyme.
Thus, there remains a need for sensitizing agents for boron neutron capture therapy.